Elevation of serum IgE and Th2-dominant airway inflammation are characteristic features of asthma. In allergic asthmatics, IgE is thought to play a central role in generating airway inflammation, by initiating signaling within mast cells and other resident airway constituents, including smooth muscle cells. Indeed, IgE has become the target of novel anti-IgE therapy intended to reduce Th2-type airway inflammation in asthma. Recently, we discovered that mice deficient with targeted disruption of the gene encoding lymphotoxin alpha (LTa -/-) are also severely deficient in both IgE and IgA, yet these mice exhibit profound spontaneous Th1-dominant airway inflammation. With age, these animals develop severe airway remodeling, with bronchial wall thickening, subepithelial fibrosis, and hypertrophy of goblet cells, myocytes, and epithelial cells. Preliminary results suggest a model in which LT deficiency causes IgE deficiency, and that IgE deficiency that skews airway responses toward Th1-type inflammation and consequent remodeling. Thus, while they act through distinct inflammatory mechanisms (Th2 vs Th1), both IgE excess and IgE deficiency each lead to asthma-like airway pathology. This raises the possibility that some asthmatics experience Th1-dominant, rather than Th2-dominant, airway inflammation. The major objective of this project is to learn the mechanisms that underlie our findings in LT-deficient mice. In particular, we seek to identify: 1) where IgE is produced and what regulates its production; 2) how LTa and IgE levels influence mast cell development and function; and 3) how LTa and IgE levels regulate the Th1-Th2 balance. Our key premise is that understanding how IgE levels regulate airway inflammation will lead to better understanding of parallel mechanisms that may operate in asthma, and guide future immunotherapy of asthma.